EP2179752B1 - Implant et son procédé de fabrication - Google Patents

Implant et son procédé de fabrication Download PDF

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Publication number
EP2179752B1
EP2179752B1 EP09170895.8A EP09170895A EP2179752B1 EP 2179752 B1 EP2179752 B1 EP 2179752B1 EP 09170895 A EP09170895 A EP 09170895A EP 2179752 B1 EP2179752 B1 EP 2179752B1
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Prior art keywords
layer
plasma
implant
approximately
chemical treatment
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German (de)
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EP2179752A3 (fr
EP2179752A2 (fr
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Ullrich Bayer
Jan Schettler
Günter Ewert
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Biotronik VI Patent AG
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Biotronik VI Patent AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/086—Phosphorus-containing materials, e.g. apatite

Definitions

  • the invention relates to a method for producing an intraluminal endoprosthesis comprising a body, the body comprising metallic material, and intraluminal endoprostheses obtainable or obtained by such a method.
  • Implants in the sense of the present invention are endovascular prostheses, for example stents.
  • implants are used more frequently as stents, which are used for the treatment of stenoses (vessel narrowing). They have a body in the form of a tubular or hollow cylindrical basic grid which is open at both longitudinal ends. The tubular base grid of such endoprosthesis is inserted into the vessel to be treated and serves to support the vessel. Stents have become established especially for the treatment of vascular diseases. By using stents narrowed areas in the vessels can be widened, resulting in a lumen gain.
  • stents or other implants can achieve an optimal vascular cross-section which is primarily necessary for successful therapy, the persistent presence of such a foreign body initiates a cascade of microbiological processes leading to gradual stenting and, in the worst case, vascular occlusion can.
  • One approach to solving this problem is to fabricate the stent or other implants from a biodegradable material.
  • Biodegradation is understood to mean hydrolytic, enzymatic and other metabolism-related degradation processes in the living organism, which are primarily caused by the body fluids which come into contact with the biodegradable material of the implant and lead to a gradual dissolution of the structures of the implant containing the biodegradable material.
  • the implant loses its mechanical integrity at a given time through this process.
  • biocorrosion is often used.
  • bioresorption covers the subsequent absorption of the degradation products by the living organism.
  • Materials suitable for the body of biodegradable implants may include, for example, polymers or metals.
  • the basic grid can consist of several of these materials. The common feature of these materials is their biodegradability.
  • suitable polymeric compounds are polymers from the group of cellulose, collagen, albumin, casein, polysaccharides (PSAC), polylactide (PLA), poly-L-lactide (PLLA), polyglycol (PGA), poly-D, L-lactide co-glycolide (PDLLA-PGA), polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV), polyalkylcarbonates, polyorthoesters, polyethylene terephthalate (PET), polymalonic acid (PML), polyanhydrides, polyphosphazenes, polyamino acids and their copolymers, and hyaluronic acid.
  • the polymers may be present in pure form, in derivatized form, in the form of blends or as copolymers.
  • Stents are already known which have coatings with different functions. Such coatings are used, for example, the release of drugs, the placement of an X-ray marker or the protection of the underlying structures.
  • the degradability should be controlled according to the desired therapy or the application of the respective implant (coronary, intracranial, renal, etc.).
  • one important target corridor is that the implant loses its integrity over a four-week to six-month period.
  • integrity ie mechanical integrity
  • the implant is mechanically still so stable that, for example, the collapse pressure only slightly, ie at most to 80% of the nominal value, has fallen off. The implant can thus still comply with its integrity, its main function, the retention of the vessel.
  • integrity may be defined by the implant being mechanically stable enough to undergo little geometric change in its loading state in the vessel, for example, not collapse significantly, ie, at least 80% of the dilation diameter under load, or in the case of a stent Has barely begun supporting struts.
  • Biodegradable magnesium implants in particular magnesium stents, have proved particularly promising for the mentioned target range of degradation, but they lose their mechanical integrity or supporting effect on the one hand too early and on the other hand have a strongly fluctuating loss of integrity in vitro and in vivo. This means that in the case of magnesium stents, the collapse pressure is reduced too fast over time or the reduction in the collapse pressure has too great a variability and is thus too indeterminable.
  • stents or other implants usually assume two states, namely a compressed state with a small diameter and an expanded state with a larger diameter.
  • the implant In the compressed state, the implant can be introduced by means of a catheter into the vessel to be supported and positioned at the site to be treated.
  • the implant At the site of treatment, the implant is then dilated, for example, by means of a balloon catheter or (when using a shape memory alloy as implant material), for example, by heating in excess of a transition temperature in the expanded state. Due to this change in diameter, the body of the implant is exposed to mechanical stress. Additional mechanical stresses on the implant may occur during or during the manufacture of the implant in or with the vessel in which the implant is inserted.
  • the coating breaks (for example, forms microcracks) during the deformation of the implant or is also partially removed. This can cause an unspecified local degradation.
  • the onset and rate of degradation are dependent on the size and distribution of microcracks resulting from the deformation, which are poorly controllable as defects. This leads to a strong dispersion in the degradation times.
  • the treatment of the implant surface with said conversion solution causes anodic oxidation of the implant. It is carried out either without the use of an external power source (external de-energized) or with a power source.
  • an external power source external de-energized
  • electrolyte compositions do not meet the expectations of degradation behavior and dilatability without layer disruption when applied to a magnesium stent.
  • a medical device such as a catheter or a stent is known in which a polymer-free coating is applied by means of a plasma electrolytic deposition (PED) process.
  • the plasma electrolytic coating is used to additionally incorporate drugs in the coating which include a drug or therapeutic agent.
  • the plasma electrolytic coating comprises plasma electrolytic oxidation (PEO), micro-arc oxidation (MAO), plasma-arc oxidation (PAO), anodic spark-oxidation and electrolytic plasma saturation (plasma electrolytic saturation PES).
  • the plasma electrolytic coating is carried out by means of pulsed AC or DC voltage at voltages between -100 V to 600 V.
  • the current densities are in the range of 0.5 to 30 A / dm 2 .
  • the publications specify a range of 10 to 100 Hz as the appropriate AC frequency range for the disclosed application.
  • the plasma electrolytic treatment involves the application of various electrical potentials between the medical device and a counter electrode that creates an electrical discharge (a spark or arc plasma micro discharge) at or near the surface of the medical device. The method given in the cited references thus does not solve the above problem.
  • the object of the present invention to provide a method for the production of an intraluminal endoprosthesis which allows a degradation of the implant in the desired target corridor.
  • the degradation should take place at a controllable time and in addition allow the dilation or deformation of the implant without significant influence on the degradation behavior.
  • the object of the invention is also to provide such an implant.
  • the present invention involves the treatment of the body surface in an aqueous electrolyte system (aqueous solution) in which plasma-chemical effects arise directly on the surface of the body of the implant.
  • aqueous electrolyte system aqueous solution
  • the microsecond stable plasma on the body surface produces reaction products that result in the formation of the first layer on the body surface.
  • the body of the implant comprises at least a part of the implant, preferably the main part of the implant, which effects the mechanical integrity of the implant.
  • the advantage of the method according to the invention is that form by the plasma-chemical treatment on the body surface of the implant hydroxides and oxides of the metallic material.
  • This layer composition upon contact with the body fluid provides a temporary corrosion protection which causes a delayed degradation of the metallic material.
  • the particles released in the course of the delayed degradation of the implant are partially incorporated by the body's own cells and / or further degraded.
  • the degradation-inhibiting layer produced by means of the method according to the invention has, as a result of the method, pores which initially naturally form corrosive weak points by which the contact with the metallic base material is made easier for the electrolyte.
  • the surface analytical investigations carried out before and after the degradation tests have shown that the hydroxide formation associated with the plasma-chemical treatment leads to a locally limited sealing of the pore surfaces.
  • the sealing of the pore bases can be detected for example on the basis of the multistage course of the pH of the electrolyte in a corrosion test (for example in artificial plasma).
  • a corrosion test for example in artificial plasma.
  • the pH increases from 7.4 to 8.5 to 8.7 in the first seven days.
  • the pH increases surprisingly from 7.4 only to 8.0.
  • This behavior shows less chemical activity of the metallic base material (especially magnesium) with the corrosive medium.
  • This effect is accompanied by a stop in the cross-sectional taper of the material of the implant body, which is already evident after seven days in metallographic cross-section.
  • This effect can be explained, for example, by the fact that hydroxides of the metallic material fill the pores in the first layer and thus the contact of the electrolyte with the metallic base material is prevented.
  • the degradation rate can be controlled by varying the layer thickness. This also opens up the possibility of adapting the degradation time of the implant to the specific implantation site (coronary, intercranial, renal etc.).
  • the method according to the invention is also characterized in that a plasma-generating alternating voltage having a frequency of at least 1 kHz is applied to the body of the implant.
  • a plasma-generating alternating voltage having a frequency of at least 1 kHz is applied to the body of the implant.
  • the aqueous solution for plasma-chemical treatment contains phosphate ions, so that in addition to the oxides and hydroxides of the underlying metallic material in the first layer and phosphates of the body material form, which provide better biocompatibility of the implant material, in particular the coating.
  • the phosphate ions originate from the addition of potassium dihydrogen phosphate and / or dipotassium hydrogen phosphate and / or potassium phosphate and / or sodium dihydrogen phosphate (dihydrate) and / or heptahydrate and / or dodecahydrate in the aqueous electrolyte.
  • the preferred concentration range is between 5 g / l and 200 g / l of the added compound in the aqueous solution.
  • a particularly preferred concentration is between 50 and 100 g / l potassium dihydrogen phosphate.
  • the body has at least one at least largely biodegradable metallic material.
  • the treatment of the implant of a biodegradable material by means of a plasmachemic process results in that upon contact with the body fluid, a temporary corrosion protection is realized, which causes a delayed degradation of the metallic material.
  • a further advantage of the method according to the invention is that non-removable surface contaminations of the base material are absorbed by the first layer and thus do not additionally influence the degradation process.
  • protruding, sometimes sharp edged exudates of the implant body are covered from the surface. This also results in increased hemo- or biocompatibility.
  • the process-related porous structure of the first layer has a high plastic deformation capacity.
  • the microcracks resulting from dilating a stent are stopped by energy accumulation or dissipation in the pores adjacent to the microcracks. There is thus no delamination of the first layer.
  • the aqueous solution contains one or more ions of Sr 2+ , which are preferably contained in a concentration of 0.05 mol / l to 2.0 mol / l of Sr 2+ in the aqueous solution.
  • strontium compounds are incorporated into the first layer, ie the surface layer of the implant. This is advantageous since, in particular, strontium carbonate is hardly soluble in water and thus forms a constituent layer that is particularly inhibiting degradation in the surface layer of the implant.
  • the strontium carbonate contained in the coating especially in cranial applications develop a drug-like effect against cerebral sclerosis.
  • a second layer is applied to at least part of the body surface before the plasma-chemical treatment, which comprises at least one element, preferably two elements, of the group consisting of tantalum, niobium, zinc, iron and aluminum, in particular nanocrystalline aluminum.
  • a coating is used in particular for implant bodies made of materials such as 316L stainless steel, nickel-titanium alloys and cobalt-chromium alloys (eg L605).
  • the materials mentioned have the disadvantage that they release nickel ions whose influence on the treated is not considered uncritical. The same applies to the extraction of vanadium ions from the alloy TiAl6V4, which is widely used in orthopedics. Such release effects are also observed when diffusion barriers of native or alien materials are applied to these materials.
  • Another aspect of the manufacture of endoprostheses that includes a desirable design includes the radiopacity of the implants. Usually, this is achieved by structural changes, for example by the installation of X-ray markers and / or the large-scale application of heavy, better radiopaque metal layers, such as gold. However, such a layer leads to a low Corrosion resistance of the composite material, as local elements form. In addition, a gold coating has too low a hardness.
  • the solution according to the invention according to the preferred exemplary embodiment consists in applying to the body surface, in particular in the case of materials of the implant body containing nickel and / or vanadium, a second layer, which is at least one element of the group consisting of tantalum, before the plasma-chemical treatment.
  • a second layer which is at least one element of the group consisting of tantalum, before the plasma-chemical treatment.
  • Niobium, zinc, iron and aluminum in particular nanocrystalline aluminum.
  • Such a layer composite comprising a second layer and an overlying first layer produced by means of plasma-chemical treatment has the advantage that a reinforced diffusion barrier is created by the metallic tantalum, niobium, zinc, iron, and / or aluminum, in particular nanocrystalline aluminum ensures biocompatibility for non-biocompatible metal ions (Ni, V).
  • the surface roughness generated by means of the first layer brings about an increased adhesion effect for subsequent, degradable or non-degradable polymeric or inorganic cover layers which can serve, for example, as active substance-releasing carrier media (pharmaceutically active substance).
  • the pore structure of the first layer can act as a fabric reservoir for pharmaceutically active substances which can be incorporated as nano- or microparticles and can serve as a lubricant to reduce the coefficient of friction in the catheter, bony growth-promoting substances such as calcium phosphates, temporary acting contrast agents or cell-growth-inhibiting radioactive substances.
  • a "pharmaceutically active substance” (or therapeutically active or active substance) is understood to mean a plant, animal or synthetic active ingredient (medicament) or a hormone which, in suitable dosage, acts as a therapeutic agent for influencing states or functions of the body. as a substitute for naturally produced by the human or animal body active ingredients, such as insulin, as well as for the elimination or to make Harmful of pathogens, tumors, cancer cells or body foreign substances use.
  • the release of the substance in the vicinity of the implant has a positive effect on the healing process or has pathological effects Tissue damage as a result of surgery is used to neutralize malady cells in oncology.
  • Such pharmaceutically active substances have, for example, an anti-inflammatory and / or antiproliferative and / or spasmolytic action, as a result of which, for example, restenoses, inflammations or (vascular) spasms can be avoided.
  • Such substances may be, for example, one or more substances of the active ingredient group of calcium channel blockers, lipid regulators (such as fibrates), immunosuppressants, calcineurin inhibitors (such as tacrolimus), antiflogistics (such as cortisone or dichlofenac), anti-inflammatory agents (such as imidazoles).
  • antiallergic agents such as oligonucleotides (such as dODN), estrogens (such as genistein), endothelial agents (such as fibrin), steroids, proteins, hormones, insulins, cytostatics, peptides, vasodilators (such as for example, Sartane) and the antiproliferative substances, the taxols or taxanes, here preferably paclitaxel, or sirolimus exist.
  • the tantalum and / or niobium-containing coating also achieves an improved radiopacity of the implant. Under certain circumstances, the use of a special X-ray marker can be avoided.
  • the high energy input during the plasma-chemical treatment also ensures that the second layer adheres very well to the body of the implant, since a large part of the arc discharges acts so deeply into the body surface that the second layer at the interface with the body Surface is firmly connected.
  • the second layer is preferably applied by means of an ionic liquid, sputtering, high-rate sputtering and / or vapor deposition.
  • the advantage of applying the second layer by means of an ionic liquid is that during application of the layer, in particular when using a binary system, micro-alloying effects take place between the material of the implant body and the applied material.
  • the microalloying forms a layer 20 which is several nanometers to a few micrometers thick and which does not form an alloy of the metals contained in the ionic liquid and the material of the implant body, which under the usual conditions of fusion metallurgy (eg due to lacking or insufficient mutual solubility) could be generated.
  • the layer combinations can be deposited both on an untreated implant and on a previously electrolytically polished implant surface.
  • Such a second layer prevents the elution of cytotoxic metal ions from the implant body, increases the corrosion resistance of the surface even in the highly deformed state and thus allows the treatment of highly reactive implant metal surfaces (eg magnesium alloy), in contact with the air contact or in the electropolishing With temporary, short-lived compounds would immediately form an oxide layer or other undesirable surfaces.
  • a further advantage of the coating by means of an ionic liquid is that the surface thus produced ensures increased corrosion resistance even in the strongly deformed state.
  • the surface of the second layer is microstructured and improves the adhesion of an overlying layer. Furthermore, it is advantageous that a second layer produced in this way prevents the diffusion of Ni, Co, V and Cr ions from the material of the implant body to the cell tissue in a long-term stable manner.
  • the coating is carried out by means of an ionic liquid which contains the extremely reaction-stable pyrrolidinium ions.
  • an ionic liquid which contains the extremely reaction-stable pyrrolidinium ions.
  • Such an ionic liquid is sufficiently stable to allow in particular a deposition of nanocrystalline aluminum.
  • the implant after the plasma-chemical coating in a solvent, preferably distilled H 2 O, rinsed and then preferably dried at a temperature of at least about 80 ° C, more preferably at least about 100 ° C, the drying preferably in a Convection oven is performed.
  • a solvent preferably distilled H 2 O
  • one or more ions selected from the group of carbonates, hydroxides and silicates are additionally contained in the aqueous solution used for the plasma-chemical treatment.
  • a buffer preferably potassium dihydrogen phosphate and / or sodium dihydrogen phosphate, is preferably contained in the aqueous solution.
  • the implant body is treated electrochemically before the plasma-chemical treatment, preferably electrochemically polished.
  • impurities are removed on the surface of the implant body, so that the plasma-chemical treatment takes place on a defined surface.
  • the electropolishing (but not necessarily) before the application of the second layer done. It can also take place after the application of the second layer and before the plasma-chemical treatment. Important is the freedom of surface contamination, which would otherwise lead to poor adhesion of the plasma-chemically applied coating.
  • the electropolishing leads to contamination-free cover layers due to large material removal effects (depth effect).
  • the plasma-chemical treatment of the implant body preferably takes place in that a pulsed, preferably positive, voltage is applied to the body, the amplitude of which exceeds at least about 90 volts for the predominant period of treatment, more preferably at least about 100 volts, and which preferably over time the treatment increases.
  • a pulsed, preferably positive, voltage is applied to the body, the amplitude of which exceeds at least about 90 volts for the predominant period of treatment, more preferably at least about 100 volts, and which preferably over time the treatment increases.
  • the plasma-chemical process is preferably carried out with a current density of at least about 8 mA / cm 2, preferably at least about 10 mA / cm 2 .
  • a post-treatment of the body of the implant in an aqueous, strongly basic sodium hydroxide solution is carried out to produce a third layer.
  • the pH range is preferably - depending on the NaOH concentration - between about 11 and about 13.8.
  • the temperature of the after-treatment solution is preferably between room temperature and 70 ° C.
  • the preferred residence time of the implant body in the sodium hydroxide solution is between 5 s and 180 s.
  • the aftertreatment seals the pore bases, which are critical from the point of view of corrosion resistance or permeability, of the first layer produced by the plasma-chemical coating, so that the third layer essentially exists in the pore grounds.
  • the after-treatment only closes the pore bases and not the complete pores, so that the positive effect of the surface roughened by the plasma-chemical treatment and the associated high adhesion to polymeric cover layers are retained. As a result, an increased corrosion resistance of the implant is achieved, which leads to a degradation and loss of integrity in a time window of 3 to 12 months, which is of interest for many treatments.
  • the sealing effect of the pore base which is based on the formation of hydroxides (for example of magnesium hydroxides in the case of a magnesium) in accordance with the invention in this preferred embodiment also has the effect of a very advantageous crack-stop mechanism. This arises due to the difference in the mechanical consistency of the material of the porous cover layer on the one hand and the material of the sealed pore base on the other. It is based on the high absorption capacity of the pore for the crack energy.
  • Microcracks for example, occur at the moment of the dilation of stents or other implants, if they are claimed beyond their plasticizing capacity in microscopic areas and lead to an uncontrolled and therefore undesirable degradation of the basic material of the implant body.
  • the cracks occurring in the preferred embodiment in the plasma-chemically generated layer consisting of mostly X-ray amorphous oxides, hydroxides and / or phosphates of the base material are collected in the pores. This is based, on the one hand, on the quiescent and, thus, the crack energy accumulating geometry of the pore per se and, on the other hand, on the hydroxide (for example magnesium hydroxide) which is arranged in the pore base and tough in comparison with the rest of the layer matrix.
  • the hydroxide for example magnesium hydroxide
  • the hydroxide layer on the base of the pores is advantageously reinforced by the aftertreatment according to the invention, so that the described crack stop mechanism functions particularly effectively. As a result, a high damage tolerance is achieved under mechanical stress, so that the degradation takes place more evenly.
  • the aftertreatment is carried out by applying ultrasound and / or blowing argon and / or nitrogen.
  • the third layer formed substantially at the bottom of the pores of the first layer has a thickness of several tens of nm.
  • a further advantage of the combination of the first and the third layer according to the invention is that no blistering and thus no lumen loss occurs in the case of advanced degradation due to the semipermeability of the layer composite or the blistering is reduced.
  • a fourth, preferably polymer-containing layer is applied to the first layer and / or the third layer, more preferably at least predominantly parylene.
  • Preferred layer thicknesses of the parylene layer are between about 0.5 and about 10 microns.
  • the permeation properties for water, chloride-containing solutions and hydrogen which are characteristic of parylene, in particular Parylene N, in conjunction with the plasma-chemically generated surface which may have been sealed on the pore surfaces, provide a surface controllable degradation behavior of the implant. This is also characterized by a uniform over the implant cross section uniforms corrosion progress.
  • the parylene layer makes an additional contribution to preventing or hindering crack propagation under mechanical stress and prevents partial delamination.
  • parylene is the name for completely linear, partially crystalline, uncrosslinked aromatic polymers.
  • the various polymers have different properties and can be divided into four basic types, namely Parylene C, Parylene D, Parylene N and Parylene F.
  • Parylene N is used for use as a fourth layer in the layer composite according to the invention.
  • the first layer and / or third layer arranged below the fourth layer leads to high adhesion of the fourth layer, so that an otherwise necessary primer treatment becomes superfluous.
  • the first layer produced by means of the plasma-chemical treatment preferably has a thickness of approximately 1 to 20 ⁇ m, preferably approximately 1 to 8 ⁇ m.
  • a layer with a thickness of about 2 to 5 microns is favored because of the higher plasticizing capacity.
  • the second layer has a layer thickness of between about 0.5 ⁇ m and about 15 ⁇ m.
  • This preferred layer thickness range is advantageous because, on the one hand, there is a sufficiently large diffusion barrier between the attacking corrosive medium (blood or plasma) and, on the other hand, no excessive impairment of the deformability (important in stent dilatation). In the case of layer thicknesses that are too high, for example, the layer would flake off during crimping or dilatation so that underlying layers and the metallic base material would come into direct contact with the corrosive media. An accelerated corrosion would be the result.
  • the first layer has pores, wherein preferably, in particular in the case of a treatment of the implant in a sodium hydroxide solution described above, a hydroxide of the metallic material or of the metallic materials of the implant body is formed on the base of the pores as the third layer.
  • the first layer preferably contains at least one compound selected from the group of phosphates, hydroxides and oxides of the biodegradable material or of the biodegradable materials, strontium carbonate, strontium phosphate.
  • a stent having a body consisting of a magnesium alloy, preferably WE43 (93% by weight of magnesium, 4% by weight of yttrium (W) and 3% by weight of rare earth metals (E) except yttrium) is provided.
  • multistage degreasing in surfactant-containing solutions and subsequent rinsing in distilled H 2 O may optionally take place before the plasma-chemical coating process.
  • the body of the implant is electrically contact-safe connected by means of a titanium or an aluminum wire to the anode of electrodes.
  • the counter electrode (cathode) consists of a rust and acid resistant steel.
  • Anode and cathode of the electrodes are connected to a voltage source capable of delivering a pulsed voltage.
  • the current density is about 10 mA / cm 2 at a frequency of at least 1 kHz.
  • a constantly increasing, pulsed bath voltage is applied.
  • characteristic bath voltage range of more than 100 V it comes to plasma chemical surface effects.
  • strontium carbonate is also formed, which is composed of the carbon of ethylenediamine, the oxygen of the aqueous electrolyte and the strontium of strontium hydroxide or strontium nitrate.
  • strontium phosphate is formed, which is a plasma chemical conversion product of potassium dihydrogen phosphate and water.
  • the layer thickness of the first layer thus produced is preferably about 1 ⁇ m to about 20 ⁇ m, more preferably between 2 ⁇ m and 8 ⁇ m, and depends essentially on the bath voltage used.
  • implants can be produced which degrade in a desired time window. Surprisingly, the degradation can be controlled by a layer which is porous.
  • the example describes the coating of non-resorbable implants of nitinol, stainless steel or cobalt-chromium alloys or degradable materials with a second layer 20 of metals containing at least one element of the group tantalum, niobium, zinc, iron and aluminum.
  • the implant is first manufactured using known technologies such as laser cutting, electropolishing, etc., so that a body 5 (see FIG. 1 ) is present. Thereafter, a coating of the surface of the body 5 with Tantalum, niobium, zinc, iron, aluminum or an alloy containing these metals.
  • the coating technologies used can be ionic liquids, sputtering, high-rate sputtering or vapor deposition.
  • the second layer 20 is prepared with tantalum on a nitinol implant by means of an ionic liquid 1-butyl-1-methylpyrrolidinium bis (trifluoromethylsulfonyl) amide of TaF 5 .
  • an ionic liquid 1-butyl-1-methylpyrrolidinium bis (trifluoromethylsulfonyl) amide of TaF 5 This results in a 0.5 to 1 micron thick tantalum layer 20, which adheres so firmly by an anodic pre-oxidation of nitinol in the ionic liquid that it is mechanically very difficult to remove.
  • a magnesium implant whose body 5 consists of a magnesium alloy can be coated with nanocrystalline aluminum in the abovementioned ionic liquid made of AlCl 3 , so that a second layer 20 containing nanocrystalline aluminum is formed.
  • the forming second layer 20 has a thickness in the range of a few micrometers.
  • the preferred layer thickness range to be set is between 0.5 and 15 ⁇ m.
  • Particularly desirable are coating parameters which lead to a uniform layer thickness distribution of the second layer 20 also on the inside or on hard-to-reach gaps and undercuts of the implant.
  • the implants are electrically connected to a thin alike wire (e.g., Ta or Nb) or a wire of Ti or Al and dipped in an aqueous electrolyte solution and contacted anodically.
  • a thin alike wire e.g., Ta or Nb
  • a wire of Ti or Al e.g., Ti or Al
  • the aqueous solution contains 100 ml / l of ethylenediamine (99%), 50 g / l of potassium dihydrogenphosphate, 10 g / l of sodium carbonate and 25 ml / l of 25% aqueous ammonia solution (% by weight).
  • the composition of the specified electrolytic solution is selected such that elements or compounds contained therein can be found on the surface of the implant after a subsequent plasma-chemical coating process.
  • the electrolyte solution is in a suitable container made of glass or plastic. This is the counter-electrode made of stainless and acid-resistant steel, which takes over the function of the cathode here.
  • the composite layer 20 produced by these plasma-chemical effects has a porous surface due to the process.
  • the pores are statistically but relatively regularly distributed and have a mean pore diameter of about 1 to 3 microns.
  • the layer is characterized by a high adhesion to the respective base material (nitinol, stainless steel, magnesium and / or cobalt-chromium alloys).
  • the thickness and the surface roughness of the surface layer according to the invention can be influenced by the process parameters described in the following examples. Thus, depending on the application, it is possible to produce both a relatively smooth, glassy or ceramic-like surface with predominantly worm-like pores or a relatively rough surface with a crater-like surface morphology offset by round pores.
  • the specific electrolyte tensions for the metals tantalum and niobium which range between 250 V and 450 V (depending on the layer thickness to be set and surface roughness), should not be exceeded. Otherwise, the plasma-chemical oxidation effects - depending on the thickness of the originally applied coating material - would reach the respective base material. The arcing phenomena occurring in this case would lead to the destruction of the composite layer composite just produced. For this reason too, the plasma-chemical process parameters are to be selected such that no complete deep oxidation of the material of the second layer 20 takes place. The oxidation should take place at most to a depth of the material that is 1 micron smaller than the original thickness of the second layer 20.
  • a remaining metallic layer material thickness of the second layer 20 of about 1 micron is ensured, which in the later application, the main part of plastic deformation (eg in a stent dilatation) will take over.
  • high-purity Ta or Nb is applied, since only highly pure elements have the plasticizing capacity necessary for the present application.
  • the current density decreases from approximately 1 A / dm 2 to approximately 50% of the initial value.
  • the process is interrupted by disconnecting the power supply and the implant provided with the second layer 20 and the first layer 10 can be removed from the electrolyte.
  • a variety of further treatments are used. These may include dipping in or spraying polymeric solutions to form a fourth layer 40 disposed on the first layer 10 having pharmaceutically active components (e.g., for vascular intervention).
  • a parylene-containing layer is applied as the fourth layer 40 (see Example 6).
  • solutions based on degradable or non-degradable polymers can be used.
  • the selection of the pharmaceutically active substance (s) is carried out according to the particular application.
  • the fourth layer can also be omitted.
  • BMPs Bone Morphogenetic Proteins
  • Another alternative fourth layer is dipped into dilute hyaluronic acid, which accelerates cartilage formation in the case of joint implants.
  • magnesium stearate-containing solutions mixture of isopropanol and magnesium stearate.
  • the magnesium stearate-containing surface which forms upon drying minimizes the coefficient of friction in the catheter and thus facilitates the release of e.g. of stents at the site of implantation.
  • the layer thicknesses of the parylene layer can be between about 0.5 ⁇ m and about 10 ⁇ m, preferably between about 0.5 ⁇ m and about 7 ⁇ m.
  • a coating with a nonabsorbable polymer with powder particles of barium (pure substance), Bismuth or tungsten or their carbides is made possible.
  • an aftertreatment with an aqueous, strongly basic sodium hydroxide solution for producing the third layer 30 arranged substantially in the pore bases (cf. FIG. 2 ), wherein the second layer 20, as in FIG. 2 represented, can also be omitted.
  • the reaction vessel is subjected to ultrasound and simultaneously injected with argon or nitrogen by means of a frit.
  • argon or nitrogen by means of a frit.
  • This process produces a 10 nm thick third layer 30 in the pore bases 12, which has the effect of a diffusion barrier or is advantageous under mechanical stress.
  • This barrier effect can be further enhanced if an oxygen plasma is applied to an implant treated in this way after an intermediate drying process.
  • the oxygen plasma causes - depending on the duration of action - a total or partial conversion of the hydroxide contained in the third layer 30 of the base material to the oxide of the base material (eg, conversion of magnesium hydroxide to magnesium oxide), in particular in the upper region of the third layer 30th
  • a plasma polymerisation with a biocompatible polymer, preferably with parylene N for the production of the fourth layer 40 then takes place in the same coating system.
  • An approximately 0.5 to 7 ⁇ m thick Parylene N layer 40 covers the implant comprehensively. The high degree of splitting also results in a deep penetration of the polymer into the pores up to the pores.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)

Claims (15)

  1. Procédé pour la fabrication d'une endoprothèse intraluminale avec un corps (5), dans lequel le corps (5) comporte un matériau métallique, comprenant les étapes suivantes :
    a) mise à disposition du corps (5) de l'endoprothèse intraluminale,
    b) traitement chimique au plasma d'au moins une partie de la surface de corps dans une solution aqueuse, en appliquant une tension alternative au corps (5) de l'endoprothèse intraluminale, laquelle présente une fréquence d'au moins environ 1 kHz, pour produire une première couche (10) sur la partie traitée de la surface du corps.
  2. Procédé selon la revendication 1, caractérisé en ce que la solution aqueuse contient des ions phosphate.
  3. Procédé selon la revendication 1 ou 2, caractérisé en ce que le corps (5) comporte au moins un matériau métallique au moins majoritairement biodégradable.
  4. Procédé selon la revendication 3, caractérisé en ce que la solution aqueuse contient un ion ou plusieurs ions Sr2+, contenus de préférence selon une concentration respective de 0,05 Mol/l à 2,0 Mol/l de Sr2+ dans la solution aqueuse.
  5. Procédé selon l'une des revendications précédentes, caractérisé en ce qu'une deuxième couche (20) est appliquée sur au moins une partie de la surface de corps avant le traitement chimique au plasma, laquelle comporte au moins un élément parmi le groupe comprenant le tantale, le niobium, le zinc, le fer et l'aluminium, dans lequel la deuxième couche (20) est appliquée au moyen d'un fluide ionique, par pulvérisation, par vaporisation à haut débit et/ou dépôt de vapeur.
  6. Procédé selon la revendication 5, caractérisé en ce que le liquide ionique contient des ions pyrrolidinium.
  7. Procédé selon l'une des revendications précédentes, caractérisé en ce que suite au traitement chimique au plasma, la première couche (10) est rincée dans un solvant, de préférence avec du H2O distillé, puis séchée de préférence à une température d'au moins environ 80°C, et mieux, d'au moins environ 100°C, le séchage étant de préférence effectué dans un four à circulation d'air.
  8. Procédé selon l'une des revendications précédentes, caractérisé en ce que la solution aqueuse comporte en outre un ou plusieurs ions choisis parmi le groupe des phosphates, des carbonates et des silicates et/ou en ce que la solution aqueuse contient un tampon, de préférence du phosphate d'hydrogène de potassium et/ou du phosphate de dihydrogène de potassium.
  9. Procédé selon l'une des revendications précédentes, caractérisé en ce que la surface de corps est traitée électrochimiquement, de préférence polie électrochimiquement, avant le traitement chimique au plasma ou avant l'application de la deuxième couche (20).
  10. Procédé selon l'une des revendications précédentes, caractérisé en ce que le traitement chimique au plasma de la surface de corps est réalisé en appliquant une tension pulsée au corps (5), dont l'amplitude dépasse au moins environ 90 V sur la majeure partie de la durée de traitement, dépassant de façon particulièrement préférentielle au moins environ 100 V, et augmentant de préférence au cours du traitement, et en ce que la densité de courant est d'au moins environ 8 mA/cm2, de préférence d'au moins environ 10 mA/cm2 pendant le traitement chimique au plasma.
  11. Procédé selon l'une des revendications précédentes, caractérisé en ce que suite au traitement chimique au plasma, un traitement ultérieur du corps (5) de l'implant est réalisé dans une solution aqueuse d'hydroxyde de natrium fortement basique, de préférence avec une valeur de pH entre environ 11 et 13,8, pour la production d'une troisième couche (30), le traitement ultérieur étant effectué en appliquant un ultrason et/ou en soufflant de l'argon et/ou de l'azote.
  12. Procédé selon l'une des revendications précédentes, caractérisé en ce que suite au traitement chimique au plasma, une quatrième couche (40) contenant de préférence un polymère et constituée de façon particulièrement préférentielle au moins majoritairement de parylène est appliquée sur la première couche (10) et/ou sur la troisième couche (30).
  13. Endoprothèse intraluminale avec un corps (5) comportant au moins un matériau métallique, lequel peut être obtenu à l'aide d'un procédé selon l'une des revendications précédentes, dans laquelle l'épaisseur de la première couche (10) produite au moyen du traitement chimique au plasma sur la surface de corps mesure entre environ 1 et environ 20 µm, de préférence entre environ 2 et environ 8 µm, et/ou la première couche (10) contient au moins un phosphate.
  14. Endoprothèse intraluminale selon la revendication 13, caractérisée en ce que la deuxième couche (20) présente une épaisseur de couche entre environ 0,5 µm et environ 15 5 µm.
  15. Endoprothèse intraluminale selon l'une des revendications 13 ou 14, caractérisée en ce que la première couche (10) comporte des pores, un hydroxyde du matériau métallique du corps d'implant étant de préférence formé en tant que troisième couche (30) sur la base poreuse (12), et/ou en ce que la première couche (10) comporte au moins une combinaison sélectionnée parmi le groupe contenant du phosphate, de l'hydroxyde et de l'oxyde du matériau métallique de préférence biodégradable ou des matériaux métalliques de préférence biodégradables, du carbone de strontium et du phosphate de strontium
EP09170895.8A 2008-10-06 2009-09-22 Implant et son procédé de fabrication Not-in-force EP2179752B1 (fr)

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US20100087914A1 (en) 2010-04-08
US8337936B2 (en) 2012-12-25
EP2179752A2 (fr) 2010-04-28

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